The overall aim of this project is to better understand the contribution of the HIV envelope protein gp120 to HIV pathogenesis. To that end, we have focused on the complex interplay between gp120 and each of the cell surface receptors to which it binds. We have focused in particular on the contribution of gp120-mediated signal transduction to HIV pathogenesis. Our previous demonstration that gp120 engages integrin alpha4beta7, which functions as the gut-homing receptor, opens up many new and potentially important questions surrounding the role if gp120 is pathogenesis. Alpha4beta7 mediates leukocyte homing to gut associated lymphoid tissue, which is a principal site of HIV replication. This suggests that gp120 interactions with alpha4beta7 expressing cells may play an important role in HIV pathogenesis. We previously determined that alpha4beta7high CD4+ T cells are highly susceptible to productive infection by HIV relative to alpha4beta7low-neg CD4+ T cells, in part because alpha4beta7high CD4+ T cells are enriched with metabolically active cells. We hypothesized that the specific affinity of gp120 for alpha4beta7 provides a mechanism for HIV to target metabolically active CD4+ T cells and that such an activity might prove critical for efficient virus propagation and dissemination following mucosal transmission. This hypothesis is currently under investigation in a non-human primate model of HIV/SIV infection. Of note, we have investigated the interaction between HIV and alpha4beta7 on primary B cells. We have learned that some of the defects associated with HIV disease result from direct interactions between gp120 and receptors on B cells.